Recent nuclear accidents and threats have highlighted the growing risk of widespread radiation exposure causing a potentially devastating public health emergency. Acute radiation syndrome (ARS) develops after total-body or partial-body irradiation at a moderate to high dose and is especially damaging to the immune system. Damage to the skin, gut, and central nervous system is also common. Accordingly, complex injuries such as burns, multi-organ injury, and trauma increase the death rate from acute radiation syndrome. Despite advances in understanding the biological basis of radiation injury, medications that effectively treat radiation injury are limited. Medical management of accidentally irradiated victims remains based on treatment with immune factors that enhance renewal of immune cells. In more severe cases, a bone marrow transplant may be performed, but complications from graft immune rejection limit the utility of this approach. Furthermore, existing treatments have limited efficacy, are difficult to administer, and are expensive to produce. Therefore, there is an urgent need to develop new drugs to treat acute radiation syndrome that are both effective and easy to deploy in an emergency radiation exposure scenario. The goal of this proposal is to test the ability of synthetic PreImplantation Factor (sPIF), a natural immune regulatory peptide, to reverse ARS in mice when treatment begins 24-48 hours after exposure to various levels of radiation. The survival and health of mice will be monitored, and blood marker profiles will be performed. Additionally, details of the molecular basis of radiation damage and sPIF's protective effects on the immune system will be examined. Specifically, mice tissues will be scored for inflammation and organ damage. The types of immune cells present and the expression of inflammatory markers and immune regulators will be determined. The purpose of these studies will be to advance the development of sPIF as a treatment for ARS and to collect the necessary data for the submission of an investigational new drug (IND) application. The use of sPIF could revolutionize the treatment of ARS. Preclinical studies have demonstrated that sPIF completely protected mice from death when administered 2 hrs following lethal radiation exposure. Significantly, the sPIF-treated mice also maintained normal blood markers, indicating sPIF's underlying protective effect on immune function. Additional studies showed sPIF accelerated recovery of white blood cells when administered 24 hours following sub-lethal radiation exposure. Significantly, this project will more fully evaluate sPIF's potential as a non-toxic, effective treatment for radiation exposure that could be easily deployed during a public health emergency.